Effect of ACE and AT-2 inhibitors on mortality and progression to microalbuminuria in a nested case-control study of diabetic nephropathy in diabetes mellitus type 2: results from the GENDIAN study.

INTRODUCTION: There is an established role of clinical risk factors such as arterial hypertension and smoking in causing cardiovascular morbidity and diabetic nephropathy (DNP). Genetic factors increase the risk for DNP. To examine the genetic risk, we initiated a case-control study with predefined follow-up examinations. We describe the study design and baseline characteristics under special consideration of comedication, and give preliminary results of the 4-year follow-up. METHODS: We enrolled all 477 patients with DNP receiving maintenance hemodialysis in 30 centers in Southern Germany between August 1999 and January 2000. As controls, we enrolled all 482 diabetes mellitus type 2 patients without urinary microalbuminuria in two examinations on consecutive days and without other signs of renal disease in a large diabetes clinic from September 2000 to September 2001. Follow-up examinations are performed 4 and 6 years after inclusion by questionnaire and telephone interview to determine mortality and new morbidity. Controls progressing to novel DNP at follow-up, as defined by semiquantitative dipstick urinary albumin/creatinine ratio > 30 mg/g, are defined as cases in the study's nested case control component. RESULTS: At study inclusion in cases and controls, respectively, mean age was 67.3 +/- 8.2 and 58.1 +/- 11.2 years and duration of diabetes mellitus was 15.6 +/- 9.6 (at dialysis initiation) and 11.0 +/- 8.6 years. 328 controls (of which 25 had died and 14 did not perform urinalysis) were subjected to follow-up at 4 years, at a mean of 3.5 +/- 0.8 years after inclusion. 51.2% (n = 148) of living controls remained normalbuminuric, 33.9% (n = 98) had microor macroalbuminuria, and in 14.9% (n = 43) the dipstick test was inconclusive. There was no significant difference in progression to micro- or macroalbuminuria between controls treated with ACE or AT-2 inhibitors at baseline or not. Renal function as estimated by the abbreviated MDRD formula declined from 86.8 +/- 21.0 to 82.5 +/- 22.3 ml/min/1.73 m2 (p < 0.001). The decline was significant in patients on ACE or AT-2 inhibitors at baseline and not in patients without such medication at baseline. DISCUSSION: GENDIAN is a large case-control study designed to evaluate clinical and genetic determinants of DNP and other complications of long-standing diabetes mellitus type 2. We observed an association of ACE or AT-2 inhibitor therapy with cardiovascular comorbidity and a significant decline in renal function after a 4-year follow-up.

Effect of HMG-CoA-reductase inhibitors on survival in type 2 diabetes patients with end stage diabetic nephropathy.

INTRODUCTION: We studied the effect of HMG-CoA-reductase inhibitor (= CSE-I) treatment on mortality in a population of hemodialysis patients with diabetic nephropathy due to type 2 diabetes. Since the efficacy of CSE-I in dialysis patients is discussed controversially, we tested the hypothesis that only patients with LDL-cholesterol > 100 mg/dl benefit from CSE-I. METHODS: We enrolled all 445 prevalent chronic hemodialysis patients with end-stage diabetic nephropathy from 30 centres in Southern Germany from August 1999 to January 2000 for prospective study until December 2003. Fasting lipid profiles prior to dialysis session and a complete clinical phenotype were determined at inclusion. We formed 2 patient groups (serum LDL > vs. < or = 100 mg/dl). Only CSE-I were used as lipid lowering therapy in our cohort. 122 Patients were on CSE-I therapy during the study. All cause mortality (ACM) was the primary end point. Survival analysis was performed by Kaplan Meier and multivariate Cox regression analysis. RESULTS: Multivariate regression analysis and Kaplan Meier survival analysis showed a decrease in risk for ACM for patients on CSE-I therapy, irrespective of lipid status (multivariate hazard ratio (= HR) 0.58; p = 0.049; ACM 72.1% (no CSE-I) vs. 59.7% (+ CSE-I); mean survival 2.37 +/- 0.08 years (no CSE-I) vs. 2.77 +/- 0.12 years (+ CSE-I), p = 0.003). In patients with LDL > 100 mg/dl, statin treatment was also associated with reduced ACM: 48.0% (+ CSE-I) vs. 70.1% (no CSE-I), (multivariate HR 0.28, CI 95% 0.11 - 0.75, p = 0.01), but not in patients with LDL < or = 100 mg/dl (HR 0.84, CI 95% 0.41 - 1.72 p = 0.63). CONCLUSION: Our data indicates that hemodialysis patients with type 2 diabetic nephropathy may benefit from statin therapy irrespective of baseline LDL-cholesterol level. Patients with LDL > 100 mg/dl benefit most when treated with CSE-I.

Effect of genetic variation on therapy with angiotensin converting enzyme inhibitors or angiotensin receptor blockers in dialysis patients.

INTRODUCTION: The role of interaction of polymorphisms in the Renin-Angiotensin-System (RAS) with angiotensin converting enzyme (ACE) or angiotensin receptor (AGTR1) inhibitors (RAS inhibitors) is unknown, as is the role of such therapy in end stage renal disease (ESRD) patients. METHODS: We enrolled all 445 prevalent patients with diabetic nephropathy receiving maintenance hemodialysis in 30 centers in Southern Germany from August 1999 to January 2000 for prospective survival analysis until December 2003. Blood pressure and medication was recorded at inclusion. We determined survival specific for allelic variants of the ACE (insertion/deletion), Angiotensinogen (M235T) and AGTR1 (A1166C) genes. The effect of therapy with RAS inhibitors at study inclusion was determined for the allelic variants of each gene. The primary end point was all cause mortality (ACM). RESULTS: For all polymorphisms, and for therapy with RAS inhibitors there was no significant effect on survival in the complete collective (n = 445), though there was an insignificant trend for improved survival in patients on AGTR1 antagonists. Increased ACM risk was associated with treatment with RAS inhibitors only in patients homozygous for the wild type AGTR1 1166A allele (HR 1.65, p = 0.01). For all other polymorphisms, therapy with RAS inhibitors had no significant effect on ACM, irrespective of genotype. Similar results were obtained in patients with systolic ventricular dysfunction. CONCLUSION: Our data do not show a survival advantage for type 2 diabetes hemodialysis patients receiving RAS inhibiting therapy. In addition, our data indicate that allelic variation in RAS genes and pharmacogenetic interaction with RAS inhibition does not affect mortality risk in diabetic hemodialysis patients.

Intracoronary formation and retention of micro aggregates of leukocytes and platelets contribute to postischemic myocardial dysfunction.

OBJECTIVE: Cardiac pump function and coronary regulation can be impaired after short-term ischemia. Recent studies with platelets (P) and neutrophils (PMN) yielded contradicting results about the "cellular" contribution to reperfusion injury. METHODS: Isolated guinea pig hearts performing pressure-volume work were employed, external heart work (EHW), aortic flow (AF), coronary flow (CF) and heart rate (HR) serving as parameters of cardiac function. After global ischemia, human blood cells were given as bolus (1 min) during reperfusion (intracoronary hematocrit 7%). Expression of specific adhesion molecules (P: CD62P, CD41; PMN: integrin CD11b) was measured on cells before and after coronary passage (FACS analysis). RESULTS: Postischemic recovery of pump function was significantly reduced in hearts with blood cell application (EHW: -cells 54 +/- 14%, +cells 41 +/-12%, p <0.05). Coronary response to bradykinin and reactive hyperemia were not effected. The blood-cell dependent functional loss was partly reduced by blocking CD18 (anti-CD 18) and completely abrogated by blockage of CD41 (lamifiban). The expression of CD11b on PMN and monocytes (M) and CD62P on platelets was significantly reduced in the coronary effluent and a significant decrease of CD41 on leukocytes occurred during coronary passage after ischemia. Increases in CD41 on PMN in the presence of lamifiban demasked intracoronary formation of micro aggregates (P/PMN). These micro aggregates were visualized by light microscopy. Electron microscopy revealed no significant microvascular plugging. CONCLUSION: 1) A specifically blood-cell induced loss of myocardial pump function has been demonstrated after short-term ischemia. 2) CD41 (= GpIIbIIIa) on P is responsible for this cardiac reperfusion damage. 3) The effect is causally linked to the formation of micro aggregates between PMN and P, but seems attenuated in the presence of erythrocytes as compared to effects reported from experiments in which PMN and P were applied singly or co-perfused. 4) Intracoronary retention of PMN, M and platelet-leukocyte micro aggregates seems to be transient, as adherence was not confirmed by electron microscopy.